PROJECT SUMMARY Cannabis is purported to be an effective pharmacotherapy for several chronic pain diagnoses, including multiple sclerosis, neuropathic pain, and cancer-related pain. However, there is a dearth of well-controlled research on use of cannabis to treat symptoms associated with rheumatoid arthritis (RA). RA is a chronic inflammatory disease that affects approximately 1.3 million Americans, a number that is increasing as the US population ages. RA is characterized by joint destruction, stiffness, swelling, and pain, leading to loss of function. In addition, key cytokines, or pro-inflammatory secreted proteins, are involved in joint injury associated with RA; specifically, TNF-? and IL-1. Pre-clinical studies indicate that cannabinoids demonstrate promising anti-arthritic properties in both human cells from RA patients and animal models of RA. Only one clinical study has investigated the effect of a cannabis plant derivative comprised of an equal ratio of two cannabinoids (i.e., ??-tetrahydrocannabinol [THC] and cannabidiol [CBD]), in oromucosal form, on pain related to RA, and reported promising results. Whole plant cannabis may be more effective than synthetic and partial formulations to treat chronic pain conditions, putatively due to its composition of hundreds of distinct cannabinoids that work in synergy to alleviate symptoms. In addition to THC, which has been shown to reduce several types of chronic pain, CBD may be particularly effective in reducing negative symptomology in RA patients due to its anti-inflammatory properties. This pilot project will investigate the impact of cannabis on pain, affect, and inflammation among RA patients (n = 66). We will administer three cannabis formulations via vaporization (placebo, low THC [<1%] /medium CBD [1-5%], medium THC [1-5%]/medium CBD [1-5%]) across three experimental sessions using a counter-balanced, double-blind, crossover design. Blood will be collected during each session (pre-vaporization, 10 minutes post-vaporization, 60 minutes post-vaporization). Self- reported pain and affect will be assessed at the same time points. The effect of cannabis on pain, affect, and inflammatory biomarkers will be assessed. This study will be the first to investigate the dose-dependent effect of cannabis on pain, affect, and markers of inflammation among patients with RA. Exploring novel and effective strategies to reduce pain and inflammation among individuals living with RA is crucial as current pharmacotherapies may not completely alleviate negative symptoms, and some, including opioids, pose high dependence liability. As states continue to legalize cannabis for medical and recreational purposes, it is essential to inform both state legislation and clinical treatment guidelines for physicians treating individuals with chronic pain. This study has the potential to guide clinical decisions pertaining to use of cannabis to treat RA symptoms with precise recommendations regarding cannabis formulation.